EP1380576A1 - Neue 1h-indazolverbindung - Google Patents

Neue 1h-indazolverbindung Download PDF

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Publication number
EP1380576A1
EP1380576A1 EP02724612A EP02724612A EP1380576A1 EP 1380576 A1 EP1380576 A1 EP 1380576A1 EP 02724612 A EP02724612 A EP 02724612A EP 02724612 A EP02724612 A EP 02724612A EP 1380576 A1 EP1380576 A1 EP 1380576A1
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group
substituted
groups
hydrate
salt
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EP1380576A4 (de
EP1380576B1 (de
Inventor
Hitoshi Oinuma
Norihito Ohi
Nobuaki Sato
Motohiro Soejima
Hidenori Seshimo
Taro Terauchi
Takashi Doko
Naohiro Kohmura
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Eisai R&D Management Co Ltd
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Eisai Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel indazole compound having an excellent inhibitory action on protein phosphatase (protein kinase), especially on JNK protein kinase.
  • MAPK mitogen-activated protein kinase
  • ERK extracellular signal-regulation kinase
  • JNK c-Jun amino-terminal kinase
  • SAPK stress-activated protein kinases
  • SAPKs have been found in rats and are JNK homologues, and it is known that isoform groups thereof each have an amino acid sequence 90% or more equivalent to that of a corresponding isoform group of JNKs (Nature, 369, 156, 1994).
  • a multitude of activators relating to MAPK have been identified recently, and it has been clarified that pathways for activating ERK, p38, and JNKs play functionally different roles, respectively.
  • the JNK system is considered to play a role as one of medically and pharmaceutically worthy intracellular signaling pathways for the following reasons.
  • the JNK system is possibly an important signaling pathway that is activated by, for example, stress factors to cells, such as tumor necrosis factor ⁇ (TNF- ⁇ ), interleukin-1 (IL-1), and other cytokines, as well as heat shock, ultraviolet rays (UV), and X-rays, and induces not only cell proliferation and/or differentiation but also apoptosis (cell death) (Science, 270, 1326, 1995).
  • stress factors to cells such as tumor necrosis factor ⁇ (TNF- ⁇ ), interleukin-1 (IL-1), and other cytokines, as well as heat shock, ultraviolet rays (UV), and X-rays, and induces not only cell proliferation and/or differentiation but also apoptosis (cell death) (Science, 270, 1326, 1995).
  • JNKs were first found as a kinase for phosphatasing orylating Ser 63 and Ser 73 at the N-terminus of c-Jun (Nature, 353, 670, 1991), but in recent, it has been clarified that JNKs phosphorylate many transcription factors such as ATF-2 and Elk-1 and regulate their activities (EMBOJ., 15, 2760, 1996).
  • JNKs include three types, JNK 1, JNK 2 and JNK 3. JNK 1 and JNK 2 are expressed in most of tissues, but JNK 3 is particularly highly expressed in the brain (Neuron, 14, 67, 1995; Neuron, 22, 667, 1999).
  • the JNK system receives attention as one of important mechanisms relating to activation of various cells, regulation of immunocytes, or apoptosis of neurons induced by various stress signals. Accordingly, compounds exhibiting inhibitory action on the JNK pathway, particularly on JNK protein kinases are expected to be useful as therapeutic agents for various immunologic diseases, inflammatory diseases, and/or neurodegenerative diseases. However, compounds having excellent JNK protein kinase inhibitory action and satisfying requirements in, for example, pharmacological activities, dosage, and safety as pharmaceutical drugs have not yet been found.
  • the present invention relates to:
  • the present invention provides a pharmaceutical composition comprising the compound according to claim 1, a salt thereof or a hydrate of them, and a pharmacologically acceptable carrier.
  • the present invention also provides use of the compound according to claim 1, a salt thereof or a hydrate of them, for producing an agent for treating or preventing a disease against which inhibition of a c-Jun amino-terminal kinaseamino-terminal kinase (JNK) is effective, an immunological disease, an inflammatory disease or a neurodegenerative disease.
  • JNK c-Jun amino-terminal kinaseamino-terminal kinase
  • the present invention further provides a method for treating or preventing a disease against which inhibition of a c-Jun amino-terminal kinase (JNK) is effective, an immunological disease, an inflammatory disease or a neurodegenerative disease, which comprises administering a pharmacologically effective amount of the compound according to claim 1, a salt thereof or a hydrate of them to a patient.
  • JNK c-Jun amino-terminal kinase
  • JNK as used in the present description means an enzyme that phosphorylates the N-terminus region of a c-Jun protein and includes, for example, JNK 1, JNK 2, and JNK 3.
  • JNKs include three types, JNK 1, JNK 2 and JNK 3.
  • JNK 1 and JNK 2 are expressed in most of tissues, but JNK 3 is particularly highly expressed in the brain (Neuron, 14, 67, 1995; Neuron, 22, 667, 1999).
  • neurodegenerative disease(s) means all of diseases generally classified as neurodegenerative diseases in the field of medicine and includes, but is not specifically limited to, "acute neurodegenerative diseases", “chronic neurodegenerative diseases”, epilepsy, hepatic encephalopathy, peripheral neuropathy, Parkinsonian syndrome, L-DOPA-induced dyskinesia in treatment of Parkinson's disease, spastic pralysis, pain, neuralgia, infectious encephalomyelitis, cerebrovascular dementia, and dementia or neurological symptom due to meningitidis.
  • the "acute neurodegenerative diseases” include, for example, acute stage of cerebrovascular disorder (e.g., subarachnoid hemorrhage and cerebral infarction), head injury, spinal code injury, neuropathy due to hypoxia, and neuropathy due to hypoglycemia.
  • the "chronic neurodegenerative diseases” include, for example, Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, and spinocerebellar degeneration.
  • immunologic disease(s) or "inflammatory disease(s)” as used in the present description means all of diseases classified as immunologic diseases in the field of medicine, and examples thereof include, but are not limited to, sepsis, chronic rheumatoid arthritis, osteoarthritis, gout, psoriasis, psoriatic arthritis, bronchitis, chronic obstructive lung disease, cystic fibrosis, insulin-dependent type I diabetes, autoimmune thyroiditis, Crohn's disease, ulcerative colitis, atopic dermatitis, asthma, allergic rhinitis, hepatitis, systemic lupus erythematosus, acute and chronic graft rejection after organ transplantation, graft versus host diseases, eczema, urticaria, myasthenia gravis, acquired immunodeficiency syndrome, idiopathic thrombocytopenic purpura, and glomerular nephritis.
  • the structural formula of a compound represents a definite isomer.
  • the present invention includes isomers such as geometrical isomers, optical isomers based on asymmetric carbon, stereoisomers and tautomers and is not limited by the description of the formula illustrated for the sake of convenience. Accordingly, although it is possible that an asymmetric carbon atom is present in a molecule and accordingly that optically active substance and racemic substance may be present, the present invention is not limited thereto but covers any of them. Further, crystal polymorphism may be present but, again, there is no limitation but any of single crystal form or a mixture will do.
  • the compound (I) or its salt related to the present invention may be an anhydride or a hydrate, and either of them are included in the scope of claim for patent in the present invention.
  • the metabolite which is generated by decomposing the compound (I) related to the present invention in vivo , and the prodrug of the compound (I) or its salt related to the present invention produce are also included in the scope of claim for patent in the present invention.
  • the salts or hydrates of the compounds of the present invention are preferably those pharmacologically acceptable.
  • halogen atom(s) includes, for example, a fluorine atom, chlorine atom, bromine atom, and iodine atom, preferably a fluorine atom and chlorine atom, and more preferably a fluorine atom.
  • C 1 -C 6 alkyl group(s) means a linear or branched alkyl group containing 1 to 6 carbon atoms and includes, for example, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group,
  • More preferred examples are methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, and n-pentyl group.
  • C 2 -C 6 alkenyl group(s) as used in the present description means a linear or branched alkenyl group containing 2 to 6 carbon atoms and includes, for example, vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl group, 2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group, 1,3-hexadienyl group, and 1,6-hexadienyl group.
  • C 2 -C 6 alkynyl group(s) as used in the present description means a linear or branched alkynyl group containing 2 to 6 carbon atoms and includes, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group, 1-ethynyl-2propynyl group, 2-methyl-3-propynyl group, 1-pentynyl group, 1-hexynyl group, 1,3-hexadiynyl group, and 1,6-hexadiynyl group.
  • C 1 -C 6 alkylene group(s) as used in the present description means a divalent group derived from the above-defined “C 1 -C 6 alkyl group” by removal of one hydrogen atom at an arbitrary position and includes, for example, methylene group, ethylene group, methylethylene group, propylene group, ethylethylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group, trimethylene group, 1-methyltrimethylene group, 1-ethyltrimethylene group, 2-methyltrimethylene group, 1,1-dimethyltrimethylene group, tetramethylene group, pentamethylene group, and hexamethylene group, of which methylene group and 1,2-ethylene group are preferred.
  • C 2 -C 6 alkenylene group(s) as used in the present description means a divalent group derived from the above-defined “C 2 -C 6 alkenyl group” by removal of one hydrogen atom and includes, for example, vinylene groups, propenylene groups, butenylene groups, pentenylene groups, and hexenylene groups.
  • Preferred examples are vinylene groups, propenylene groups, butenylene groups, and pentenylene groups, of which vinylene groups, propenylene groups, and butenylene groups are more preferred.
  • 1,2-vinylene group and 1,3-propenylene group are further more preferred.
  • C 2 -C 6 alkynylene group(s) means a divalent group derived from the above-defined “C 2 -C 6 alkynyl group” by removal of further one hydrogen atom and includes, for example, ethynylene group, propynylene groups, butynylene groups, pentynylene groups, and hexynylene groups.
  • Preferred examples are ethynylene group, propynylene groups, butynylene groups, and pentynylene groups, of which ethynylene group, propynylene groups, and butynylene groups are more preferred.
  • ethynylene group and propynylene groups are further more preferred, of which ethynylene group is most preferred.
  • C 3 -C 8 cycloalkyl group(s) as used in the present description means three to eight aliphatic cyclic hydrocarbon groups and includes, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctyl group, of which cyclopropyl group and cyclobutyl group are preferred.
  • C 3 -C 8 cycloalkenyl group(s) as used in the present description means a C 3 -C 8 cycloalkenyl group comprising 3 to 8 carbon atoms and includes, for example, cyclopenten-3-yl, cyclohexen-1-yl, and cyclohexen-3-yl.
  • C 1 -C 6 alkoxy group(s) as used in the present description means an oxy group combined with the above-defined "C 1 -C 6 alkyl group” and includes, for example, methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group, n-hexoxy group, iso-hexoxy group, 1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group,
  • C 2 -C 6 alkenyloxy group (s) as used in the present description means an oxy group combined with the above-defined "C 2 -C 6 alkenyl group”.
  • C 2 -C 6 alkenylthio group(s) as used in the present description means a thio group combined with the above-defined "C 2 -C 6 alkenyl group”.
  • C 1 -C 6 alkoxycarbonyl group(s) as used in the present description means a carbonyl group combined with the above-defined “C 1 -C 6 alkoxy group” and includes, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, sec-butoxycarbonyl group, and t-butoxycarbonyl group.
  • C 2 -C 7 acyl group(s) as used in the present description means a carbonyl group combined with the above-defined “C 1 -C 6 alkyl group” and includes, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, and pivaloyl group.
  • C 1 -C 6 alkylcarbamoyl group(s) includes, for example, methylcarbamoyl group, ethylcarbamoyl group, n -propylcarbamoyl group, iso -propylcarbamoyl group, n -butylcarbamoyl group, iso -butylcarbamoyl group, sec -butylcarbamoyl group, tert -butylcarbamoyl group, n -pentylcarbamoyl group, 1,1-dimethylpropylcarbamoyl group, 1,2-dimethylpropylcarbamoyl group, 2,2-dimethylpropylcarbamoyl group, 1-ethylpropylcarbamoyl group, 2-ethylpropylcarbamoyl group, n-hexylcarbamo
  • C 1 -C 6 alkylcarbonyloxy group(s) means an oxy group combined with the above-defined “C 2 -C 7 acyl group” and includes, for example, methylcarbonyloxy group, ethylcarbonyloxy group, n -propylcarbonyloxy group, iso- propylcarbonyloxy group, n -butylcarbonyloxy group, iso -butylcarbonyloxy group, sec -butylcarbonyloxy group, tert -butylcarbonyloxy group, n -pentylcarbonyloxy group, 1,1-dimethylpropylcarbonyloxy group, 1,2-dimethylpropylcarbonyloxy group, 2,2-dimethylpropylcarbonyloxy group, 1-ethylpropylcarbonyloxy group, 2-ethylpropylcarbonyloxy group, n-hexylcarbonyloxy group, 1-methyl-2-e
  • C 1 -C 6 alkylsulfonyl group(s) means a sulfonyl group combined with the above-defined "C 1 -C 6 alkyl group” and includes, for example, methylsulfonyl group, ethylsulfonyl group, n -propylsulfonyl group, iso -propylsulfonyl group, n -butylsulfonyl group, iso -butylsulfonyl group, sec -butylsulfonyl group, tert -butylsulfonyl group, n -pentylsulfonyl group, 1,1-dimethylpropylsulfonyl group, 1,2-dimethylpropylsulfonyl group, 2,2-dimethylpropylsulfonyl group, 1-ethylpropylsulfony
  • C 1 -C 6 alkylsulfenyl group(s) means a sulfenyl group combined with the above-defined “C 1 -C 6 alkyl group” and includes, for example, methylsulfenyl group, ethylsulfenyl group, n -propylsulfenyl group, iso -propylsulfenyl group, n -butylsulfenyl group, iso -butylsulfenyl group, sec -butylsulfenyl group, tert -butylsulfenyl group, n -pentylsulfenyl group, 1,1-dimethylpropylsulfenyl group, 1,2-dimethylpropylsulfenyl group, 2,2-dimethylpropylsulfenyl group, 1-ethylpropylsulfeny
  • C 1 -C 6 alkylthio group(s) means a thio group combined with the above-defined "C 1 -C 6 alkyl group” and includes, for example, methylthio group, ethylthio group, n -propylthio group, iso -propylthio group, n -butylthio group, iso -butylthio group, sec-butylthio group, tert -butylthio group, n -pentylthio group, 1,1-dimethylpropylthio group, 1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group, 1-ethylpropylthio group, 2-ethylpropylthio group, n-hexylthio group, 1-methyl-2-ethylpropylthio group, 1-ethyl-2-methylpropylthio group, 1,1,2-trimethyl
  • C 6 -C 14 aromatic cyclic hydrocarbon group(s) as used in the present description means an aromatic cyclic hydrocarbon group comprising 6 to 14 carbon atoms and includes monocyclic groups as well as bicyclic groups, tricyclic groups, and other condensed rings.
  • Examples of these groups include phenyl group, indenyl groups, 1-naphthyl group, 2-naphthyl group, azulenyl groups, heptalenyl groups, biphenyl groups, indacenyl groups, acenaphthyl groups, fluorenyl groups, phenalenyl groups, phenanthrenyl groups, anthracenyl groups, cyclopentacyclooctenyl groups, and benzocyclooctenyl groups.
  • phenyl group, 1-naphthyl group and 2-naphthyl group are preferred, and phenyl group, indenyl group and 2-naphthyl group are more preferred.
  • C 6 -C 14 aryloxy group(s) as used in the present description means an oxy group combined with the above-defined “C 6 -C 14 aromatic cyclic hydrocarbon group”.
  • 5- to 14-membered aromatic heterocyclic group(s) as used in the present description means a monocyclic, bicyclic, or tricyclic 5- to 14-membered heterocyclic group containing one or more hetero atoms selected from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms.
  • Examples of the group include 1) nitrogen-containing aromatic heterocyclic groups such as pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, indolizinyl group, purinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolidyl group, phthalazyl group, naphthyridinyl group, quinoxalyl group, quinazolinyl group, cinnolinyl group, pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group, carb
  • 5- to 14-membered non-aromatic heterocyclic group(s) as used in the present description means a non-aromatic heterocyclic group 1) which comprises 5 to 14 atoms, 2) which contains one or more hetero atoms as the atoms constituting the ring, 3) which may contain one to three carbonyl groups, and 4) which is a monocyclic, bicyclic or tricyclic ring.
  • Examples of the group include pyrrolidyl group, pyrrolyl group, piperidyl group, piperazyl group, imidazolyl group, pyrazolidyl group, imidazolidyl group, morpholyl group, tetrahydrofuryl group, tetrahydropyranyl group, aziridinyl group, oxiranyl group, and oxathiolanyl group.
  • the non-aromatic heterocyclic group includes groups derived from a pyridone ring and non-aromatic condensed rings such as groups derived from phthalimide ring, or succinimide ring.
  • Preferred examples of these groups are pyrrolidyl group, pyrrolyl group, piperidyl group, piperazyl group, imidazolyl group, pyrazolidyl group, imidazolidyl group, morpholyl group, tetrahydrofuryl group, tetrahydropyranyl group, aziridinyl group, oxiranyl group, and oxathiolanyl group.
  • 5- to 10-membered aromatic heterocyclic group(s) as used in the present description means a monocyclic or bicyclic aromatic heterocyclic group, whose ring comprises 5 to 10 atoms including one or more hetero atoms.
  • Examples of the group include 1) nitrogen-containing aromatic heterocyclic groups such as pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, indolizinyl group, purinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolidyl group, phthalazyl group, naphthyridinyl group, quinoxalyl group, quinazolinyl group, cinnolinyl group, pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, imidazopyridinyl group, imidazopyrimidinyl group
  • Preferred examples of the group are pyrrolyl group, furyl group, thienyl group, pyridyl group, benzothienyl group, benzryl group, indolyl group, benzolyl group, and indazolyl group, of which furyl group, thienyl group, benzothienyl group and benzofuryl group are more preferred.
  • 5- or 6-membered aromatic heterocyclic group(s) means a monocyclic aromatic heterocyclic group, whose ring comprises 5 or 6 atoms including one or more hetero atoms.
  • the group include pyrrolyl group, imidazolyl group, pyrazolyl group, 1,2,3-triazolyl group, pyridyl group, pyridazyl group, pyrimidinyl group, pyrazinyl group, furyl group, thienyl group, thiazolyl group, oxazolyl group, and isoxazolyl group, of which pyrrolyl group, pyridyl group, furyl group and thienyl group are preferred. Among them, furyl group and thienyl group are more preferred.
  • 5- or 6-membered non-aromatic heterocyclic group(s) as used in the present description means a 5- or 6-membered heterocyclic group containing one or more hetero atoms selected from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms.
  • Examples of the group include piperidyl group, piperazyl group, morpholyl group, thiomorpholyl group, tetrahydro-2-pyron-yl group, tetrahydropyran-yl groups, tetrahydrothiopyran-yl groups, piperidin-2-one-yl groups, tetrahydrofuran-yl group, tetrahydrothiophen-yl group, pyrrolidinyl group, tetrahydrofuran-2-one-yl groups, and pyrrolidin-2-one-yl groups.
  • Preferred examples of the "5- or 6-membered nonaromatic heterocyclic group" are piperidyl group, piperazyl group, morpholyl group, thiomorpholyl group, tetrahydro-2-pyron-yl groups, tetrahydropyran-yl groups, tetrahydrothiopyran-yl groups, and piperidin-2-one-yl groups.
  • 5-membered non-aromatic heterocyclic group(s) means a 5-membered heterocyclic group containing one or more hetero atoms selected from the group consisting of nitrogen atoms, sulfur atoms, and oxygen atoms and concretely means, for example, tetrahydrofuran-yl group, tetrahydrothiophen-yl group, pyrrolidinyl group, tetrahydrofuran-2-one-yl groups, or pyrrolidin-2-one-yl groups.
  • amino group(s) as used in the present description means a group represented by the formula -NH 2 .
  • amide group(s) as used in the present description means a group represented by the formula -CO-NH 2 .
  • furyl group as used in the present description means 2-furyl group or 3-furyl group, of which 2-furyl group is preferred.
  • thienyl group as used in the present description means 2-thienyl group or 3-thienyl group, of which 2-thienyl group is preferred.
  • pyrrolyl group as used in the present description means 1-pyrrolyl group, 2-pyrrolyl group, or 3-pyrrolyl group, of which 2-pyrrolyl group is preferred.
  • tetrahydrofuran-yl group as used in the present description means tetrahydrofuran-2-yl group or tetrahydrofuran-3-yl group, of which tetrahydrofuran-2-yl group is preferred.
  • tetrahydrothiophen -yl group as used in the present description means tetrahydrothiophen-2-yl group or tetrahydrothiophen-3-yl group, of which tetrahydrothiophen-2-yl group is preferred.
  • pyrrolidinyl group as used in the present description means 1-pyrrolidinyl group, 2-pyrrolidinyl group, or 3-pyrrolidinyl group, of which 2-pyrrolidinyl group is preferred.
  • tetrahydrofuran-2-one-yl group as used in the present description means tetrahydrofuran-2-one-3-yl group, tetrahydrofuran-2-one-4-yl group, or tetrahydrofuran-2-one-5-yl group, of which tetrahydrofuran-2-one-5-yl group is preferred.
  • pyrrolidin-2-one-yl group as used in the present description means pyrrolidin-2-one-1-yl group, pyrrolidin-2-one-3-yl group, pyrrolidin-2-one-4-yl group, or pyrrolidin-2-one-5-yl group, of which pyrrolidin-2-one-5-yl group is preferred.
  • quinolyl group means a monovalent group derived from a quinoline ring by removal of any one hydrogen atom and includes, for example, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, and 8-quinolyl group, of which 2-quinolyl group is preferred.
  • substituents (6) to (23) as the substituent in "may be substituted" the amino group, C 1 -C 6 alkyl groups, C 2 -C 6 alkenyl groups, C 2 -C 6 alkynyl groups, C 3 -C 8 cycloalkyl groups, C 3 -C 8 cycloalkenyl groups, C 1 -C 6 alkoxy groups, C 1 -C 6 alkenyloxy groups, C 1 -C 6 alkylthio groups, C 1 -C 6 alkenylthio groups, C 1 -C 14 aryloxy groups, C 2 -C 7 acyl groups, C 6 -C 14 aromatic cyclic hydrocarbon groups, 5- to 14-membered non-aromatic cyclic hydrocarbon groups or 5- to 14-membered aromatic heterocyclic groups, amide group, sulfonyl groups each having a C 1 -C 6 aliphatic hydrocarbon group as a substituent, or sulf
  • substituent in the term "may be substituted" as used in the present description include halogen atoms, nitrile group, C 1 -C 6 alkyl groups, C 3 -C 8 cycloalkyl groups, C 1 -C 6 alkoxy groups, and trifluoromethyl group.
  • substituent in the term "may be substituted" as used in the present description include fluorine atom, cyclopropyl group, trifluoromethyl group, and methoxy group.
  • R is a C 1 -C 8 alkyl group
  • R 1 , R 2 , R 4 , and R 5 have the same meanings as defined above
  • R 3 is a group represented by the formula -L-X-Y (wherein L, X and Y have the same meanings as the above-defined L, X and Y);
  • T 1 is a hydrogen atom, a bromine atom or an iodine atom;
  • T 2 is a halogen atom;
  • T 3 is a sulfonate or a halogen atom;
  • T 4 is a hetero atom (oxygen atom, nitrogen atom or sulfur atom);
  • "Pro" represents a protecting group;
  • Q is a C 1 -C 8 alkyl group;
  • Q 1 , Q 2 and Q 3 each independently represent a C 1 -C 8 alkyl group
  • the compound (I) can be produced by treating the fluorobenzene 1 with, for example, an alkyllithium or lithium amide to thereby yield a metal aryl, allowing the metal aryl to react with an arylaldehyde to thereby yield the alcohol 2, oxidizing the alcohol 2 into the ketone 3, and then closing the indazole ring with hydrazine.
  • the alkyllithium for converting the fluorobenzene 1 to the metal aryl includes, for example, n -butyllithium, sec -butyllithium, tert -butyllithium, and phenyllithium.
  • an additive such as N,N,N',N'-tetramethylethylenediamine and hexamethylphosphoramide can be added.
  • the lithium amide includes, for example, lithium diisopropylamide, and lithium 2,2,6,6-tetramethylpiperidide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and preferred examples thereof are ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene and toluene.
  • a reaction temperature is from -78°C to room temperature.
  • Oxidizing agents for oxidizing the alcohol compound 2 include, for example, manganese dioxide, sulfur trioxide-pyridine complex, N-methylmorpholine-N-oxide, and chromic acid oxidizing agents. The oxidation can also be performed by Swern oxidation or Moffat oxidation. Solvents for use herein can be any solvents that are not involved in the reaction and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from -78°C to the reflux temperature of the solvent.
  • the reaction for cyclization of the compound 3 with hydrazine monohydrate can be performed in the absence of, or in the presence of, a solvent.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, alcohol solvents such as methanol, ethanol or propanol, as well as pyridine, dimethyl sulfoxide, benzene, and toluene.
  • the amount of the hydrazine monohydrate is from 2 to 20 equivalents to the raw material.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the compound 2 can also be produced by Production Process 2. Initially, the fluorobenzene 1 is converted into to a metal aryl by the procedure of Production Process 1, and the metal aryl is allowed to react with a formylation agent to yield the compound 4.
  • the formylation agent includes, for example, dimethylformamide, N-formylpiperidine, and methylphenylformamide.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene and toluene.
  • a reaction temperature is from -78°C to room temperature.
  • the compound 2 can be produced by allowing the compound 4 to react with a metal aryl or metal halogenoaryl.
  • the metal aryl or metal halogenoaryl can be easily prepared, for example, by treating a halogenoaryl using an alkyllithium, magnesium or zinc into an aryllithium or metal halogenoaryl.
  • the alkyllithium includes, for example, n -butyllithium, sec -butyllithium, tert-butyllithium, and phenyllithium. Where necessary, ar additive such as N,N,N',N'-tetramethylethylenediamine and hexamethylphosphoramide can be added.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene and toluene
  • ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane
  • a reaction temperature is from -78°C to room temperature.
  • the compound (I) can also be produced by halogenating the 3-position of the indazole compound 5 to yield the compound 6, protecting the 1-position of the compound 6 to yield the compound 7, subjecting the compound 7 to Suzuki coupling with an arylboronic acid to yield the compound 8, and deprotecting the 1-position of the compound 8.
  • Reagents for halogenating the 3-position include, for example, N -bromosuccinimide, N -iodosuccinimide, N -chlorosuccinimide, and bromine.
  • a radical reaction initiator such as 2,2'-azobisisobutyronitrile and benzoyl peroxide can be added.
  • the amount of the halogenation reagent is from 1.05 to 1.2 equivalents to the raw material.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • Protecting groups for the 1-position include, for example, tert -butyloxycarbonyl group, p -toluenesulfonyl group, triphenylmethyl group, and methoxymethyl group.
  • the tert -butyloxycarbonyl group or p -toluenesulfonyl group can be introduced by allowing the compound 6 to react with di-tert-butyl dicarbonate or p-toluenesulfonyl chloride in the presence of a base.
  • bases are not specifically limited but preferred examples are triethylamine and 4- N,N -dimethylaminopyridine.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, halogenated hydrocarbons scuh as dichloromethane or chloroform, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the triphenylmethyl group or methoxymethyl group can be introduced by allowing the compound 6 to react with chlorotriphenylmethane or chloromethyl methyl ether in the presence of a base.
  • bases are not specifically limited, but preferred examples are sodium hydride, potassium tert -butoxide, lithium diisopropylamide, potassium carbonate, and sodium hydroxide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from -20°C to the reflux temperature of the solvent.
  • arylboronic acids for use in Suzuki coupling those commercially available will be purchased, and those not commercially available can be easily prepared according to a conventional procedure.
  • Such an arylboronic acid can be prepared, for example, by treating a halogenoaryl with an alkyllithium, magnesium or zinc to convert the same into an aryllithium or a metal halogenoaryl, allowing the aryllithium or metal halogenoaryl to react with trialkyl-borate into a boric ester, and hydrolyzing the boric ester.
  • the alkyllithium includes, for example, n -butyllithium, sec -butyllithium, tert -butyllithium, and phenyllithium.
  • an additive such as N,N,N',N'-tetramethylethylenediamine, and hexamethylphosphoramide can be added.
  • the boric ester formed as a result of the reaction between the aryllithium and the trialkyl-boric acid can be hydrolyzed by adding water or by using an acid such as hydrochloric acid or sulfuric acid.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, of which ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane are preferred.
  • a reaction temperature is from -78°C to room temperature.
  • the amount of the arylboronic acid for use in Suzuki coupling is from 1 to 3 equivalents to the raw material.
  • Catalysts for use herein include, for example, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), and tetrakis(triphenylphosphine)palladium(0).
  • the amount of the catalyst is about 5% by mole relative to the raw material. Where necessary, a phosphine ligand in an amount of two times by mole that of the catalyst can be added.
  • Such phosphine ligands include, for example, tri- tert -butylphosphine, 2-(di- tert -butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, and triphenylphosphine.
  • bases for use herein are sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and potassium fluoride.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, dimethylformamide, N -methylpyrrolidone, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, and toluene.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the tert -butyloxycarbonyl group and triphenylmethyl group can be easily deprotected (removed) by using an acid.
  • Such acids include, for example, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.
  • a radical scavenger such as thiophenol or tri- iso -propylsilane can be added.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, alcohol solvents such as methanol or ethanol, and anisole.
  • a reaction temperature is from -20°C to the reflux temperature of the solvent.
  • the tert -butyloxycarbonyl group and p-toluenesulfonyl group can also be easily deprotected by using a base.
  • bases include, but are not specifically limited to, aqueous sodium hydroxide and aqueous potassium hydroxide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, alcohol solvents such as methanol or ethanol, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane.
  • a reaction temperature is room temperature to the reflux temperature of the solvent.
  • the methoxymethyl group can be deprotected by treating the compound with an acid and treating the residual aminal with aqueous ammonia.
  • the compound 8 can also be obtained by converting the compound 7 into the boronic acid 9 and subjecting the boronic acid 9 to Suzuki coupling with an aryl halide or aryl sulfonate.
  • the boronic acid 9 can be obtained by converting the compound 7 into an aryllithium, allowing the aryllithium to react with trialkyl-borate to yield a boric ester, and hydrolyzing the boric ester.
  • the alkyllithium for converting the compound 7 into an aryllithium includes, for example, n -butyllithium, sec -butyllithium, tert -butyllithium, and phenyllithium.
  • an additive such as N,N,N',N'-tetramethylethylenediamine and hexamethylphosphoramide can be added.
  • the boric ester formed as a result of the reaction between the aryllithium and the trialkyl borate can be hydrolyzed by adding water or by using an acid such as hydrochloric acid or sulfuric acid.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, of which ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane are preferred.
  • a reaction temperature is from -78°C to room temperature.
  • the compound 8 can be produced by subjecting the boronic acid 9 and an aryl halide or aryl sulfonate to Suzuki coupling under the conditions of Production Process 3.
  • the compound 8 can also be produced by Stille coupling as shown in Production Process 5.
  • aryltrialkyltins for use in Stille coupling those commercially available will be purchased and those not commercially available can be easily prepared.
  • Such an aryltrialkyltin can be prepared, for example, by treating a halogenoaryl with an alkyllithium, magnesium, or zinc to thereby yield an aryllithium or metal halogenoaryl, and allowing the aryllithium or metal halogenoaryl to react with a chlorotrialkyltin or hexaalkylditin.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, of which ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane are preferred.
  • a reaction temperature is from -78°C to room temperature.
  • the amount of the aryltrialkyltin for use in Stille coupling is from 1 to 3 equivalents to the raw material.
  • Catalysts for use herein include, for example, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), and tetrakis(triphenylphosphine)palladium(0).
  • the amount of the catalyst is about 5% by mole relative to the raw material.
  • a phosphine ligand in an amount of two times by mole that of the catalyst can be added.
  • Such phosphine ligands include, for example, tri- tert -butylphosphine, 2-(di- tert -butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, and triphenylphosphine.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, dimethylformamide, N -methylpyrrolidone, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, toluene, and xylenes.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the compound 8 can also be obtained by converting the compound 7 into the tin compound 10, and subjecting the tin compound 10 to Stille coupling with an aryl halide or aryl sulfonate.
  • the tin compound 10 can be obtained by converting the compound 7 into an aryllithium under the same conditions as in Production Process 4, and allowing the aryllithium to react with a chlorotrialkyltin or hexaalkylditin.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, of which ether solvents diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane are preferred.
  • a reaction temperature is from -78°C to room temperature.
  • the compound 8 can be produced by subjecting the tin compound 10 and an aryl halide or aryl sulfonate to Stille coupling under conditions of Production Process 5.
  • the compound (I) can also be produced by subjecting the compound 6 in which the 1-position is not protected to Stille coupling under conditions of Production Process 5, as shown in Production Process 7.
  • the compound 8 can also be produced by subjecting to Stille coupling with tributyl(1-ethoxyvinyl)tin, treating the resulting compound with N-bromosuccinimide to yield the bromoacetyl 11, and converting the bromoacetyl 11 to an aromatic ring, as shown in Production Process 8.
  • the tributyl(1-ethoxyvinyl)tin for use in Stille coupling is commercially available.
  • the amount of the tributyl(1-ethoxyvinyl)tin is from 1 to 3 equivalents to the raw material.
  • Catalysts for use herein are not specifically limited, of which tetrakis(triphenylphosphine)palladium(0) is preferred.
  • the amount of the catalyst is about 5% by mole relative to the raw material.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and preferred examples thereof are tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, toluene, and xylenes.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the bromination can be performed by exchanging the solvent with tetrahydrofuran or dioxane, and adding about 1 equivalent of N-bromosuccinimide.
  • the compound 11 can be converted into an aromatic ring by allowing the compound to react with, for example, 2-aminopyridine or thiourea in the presence of a base.
  • Such bases include, but are not specifically limited to, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, and sodium hydride.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, alcohol solvents methanol or ethanol, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally 0°C to the reflux temperature of the solvent.
  • the compound 8 can also be produced by subjecting the compound 7 to Sonogashira coupling with trimethylsilylacetylene, detrimethylsililating the resulting compound to yield the compound 12, subjecting the compound 12 to coupling with the halogenated aromatic cyclic compound 13 having a hydroxyl group, amino group or thiol group at the ortho-position, each of which may be protected by a protecting group, and aromatically cyclizing the resulting compound under the same conditions after deprotecting the protecting group, if any.
  • the trimethylsilylacetylene for use in Sonogashira coupling is commercially available. The amount of the trimethylsilylacetylene is from 1 to 3 equivalents to the raw material.
  • Catalysts for use herein include, but are not specifically limited to, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), and tetrakis(triphenylphosphine)palladium(0).
  • the amount of the catalyst is about 10% by mole relative to the raw material.
  • an additive such as copper(I) iodide or triphenylphosphine can be added in an amount 1 to 2 times that of the catalyst.
  • Bases for use herein include, but are not specifically limited to, triethylamine, diisopropylamine, and piperidine.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, of which dimethylformamide, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, toluene, and xylenes are preferred.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the detrimethylsilanization can be easily performed by using a fluorine anion or an acid.
  • fluorine anions for use herein include, for example, tetrabutylammonium fluoride, hydrogen fluoride, potassium fluoride, and cesium fluoride.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, alcohol solvents such as methanol or ethanol, water, diethyl ether, tetrahydrofuran, dioxane, and toluene.
  • a reaction temperature is from -20°C to the reflux temperature of the solvent.
  • Acids for use herein include, for example, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, alcohol solvents such as methanol or ethanol, diethyl ether, and tetrahydrofuran.
  • a reaction temperature is from -20°C to the reflux temperature of the solvent.
  • those commercially available will be purchased, and those not commercially available can be produced, for example, by protecting a hetero atom of an aromatic cyclic compound having a hydroxyl group, amino group or thiol group, treating the protected compound with an alkyllithium or lithium amide to yield a metal aryl, and halogenating the metal aryl.
  • Protecting groups for T 4 include, for example, tert -butyloxycarbonyl group, pivaloyl group, and methoxymethyl group. These protecting groups can be introduced by allowing an aromatic cyclic compound having a hydroxyl group, amino group or thiol group to react with di- tert -butyl dicarbonate, pivaloyl chloride or chloromethoxymethyl in the presence of a base.
  • bases for use herein include, but are not specifically limited to, triethylamine, 4- N,N -dimethylaminopyridine, sodium hydride, potassium tert-butoxide, lithium diisopropylamide, potassium carbonate, and sodium hydroxide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, halogenated hydrocarbons such as dichloromethane or chloroform, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the alkyllithium for converting the aromatic cyclic compound having the protected T 4 into the metal aryl includes, for example, n -butyllithium, sec-butyllithium, , tert -butyllithium, and phenyllithium. Where necessary, an additive such as N,N,N',N' -tetramethylethylenediamine or hexamethylphosphoramide can be added.
  • the lithium amide includes, for example, lithium diisopropylamide, and lithium 2,2,6,6-tetramethylpiperidide.
  • Preferred examples of the halogenating agent are iodine, N -iodosuccinimide, bromine, and N -bromosuccinimide.
  • Solvents for use herein are not specifically limited, as long as they are inert in the reaction, and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene and toluene.
  • a reaction temperature is from -78°C to room temperature.
  • the amount of the compound 13 for use in the coupling reaction between the compounds 12 and 13 is from 1 to 2 equivalents to the raw material 12.
  • Catalysts for use herein include, but are not specifically limited to, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), and tetrakis(triphenylphosphine)palladium(0).
  • the amount of the catalyst is about 10% by mole relative to the raw material.
  • an additive such as copper(I) iodide or triphenylphosphine can be added in an amount 1 to 2 times that of the catalyst.
  • Bases for use herein include, but are not specifically limited to, triethylamine, diisopropylamine, and piperidine. Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, of which dimethylformamide, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, toluene, and xylenes are preferred.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent. When the hetero atom of the compound 13 is not protected, the compound can undergo aromatic cyclization under these conditions.
  • the protecting group of T 4 can be easily deprotected by using an acid or a base.
  • acids include, for example, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, halogenated hydrocarbons dichloromethane or chloroform, alcohol solvents such as methanol or ethanol.
  • a reaction temperature is from -20°C to the reflux temperature of the solvent.
  • the base is not specifically limited and includes, for example, aqueous sodium hydroxide and aqueous potassium hydroxide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, alcohol solvents methanol or ethanol, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane.
  • a reaction temperature is from room temperature to the reflux temperature of the solvent.
  • the compound 8 can also be produced by subjecting the compound 7 to coupling with the compound 14, deprotecting the coupling product to yield the compound 15, and aromatically cyclizing the compound 15, as shown in Production Process 10.
  • the compound 14 can be synthetically prepared by subjecting the compound 13 to Sonogashira coupling with trimethylsilylacetylene, and detrimethylsilylating the coupling product.
  • the trimethylsilylacetylene for use in Sonogashira coupling is commercially available.
  • the amount of the trimethylsilylacetylene is from 1 to 3 equivalents to the raw material.
  • Catalysts for use herein include, but are not specifically limited to, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), and tetrakis(triphenylphosphine)palladium(0).
  • the amount of the catalyst is about 10% by mole relative to the raw material.
  • an additive such as copper(I) iodide or triphenylphosphine can be added in an amount 1 to 2 times that of the catalyst.
  • Bases for use herein include, but are not specifically limited to, triethylamine, diisopropylamine, and piperidine.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, of which dimethylformamide, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, toluene, and xylenes are preferred.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the detrimethylsilanization can be easily performed by using a fluorine anion or an acid.
  • fluorine anions for use herein include, for example, tetrabutylammonium fluoride, hydrogen fluoride, potassium fluoride, and cesium fluoride.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, halogenated hydrocarbons dichloromethane or chloroform, alcohol solvents such as methanol or ethanol, water, diethyl ether, tetrahydrofuran, dioxane, and toluene.
  • a reaction temperature is from -20°C to the reflux temperature of the solvent.
  • Acids for use herein include, for example, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, alcohol solvents such as methanol or ethanol.
  • a reaction temperature is from -20°C to the reflux temperature of the solvent.
  • the amount of the compound 14 in the coupling reaction between the compounds 14 and 7 is from 1 to 2 equivalents to the raw material 7.
  • Catalysts for use herein include, but are not specifically limited to, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), and tetrakis(triphenylphosphine)palladium(0).
  • the amount of the catalyst is about 10% by mole relative to the raw material.
  • an additive such as copper(I) iodide or triphenylphosphine can be added in an amount 1 to 2 times that of the catalyst.
  • Bases for use herein include, but are not specifically limited to, triethylamine, diisopropylamine, and piperidine. Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, of which dimethylformamide, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, toluene, and xylenes are preferred.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the protecting group of T 4 can be easily deprotected by using an acid or a base.
  • acids include, for example, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, alcohol solvents such as methanol or ethanol.
  • a reaction temperature is from -20°C to the reflux temperature of the solvent.
  • the base is not specifically limited and includes, for example, aqueous sodium hydroxide and aqueous potassium hydroxide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, alcohol solvents such as methanol or ethanol, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane.
  • a reaction temperature is from room temperature to the reflux temperature of the solvent.
  • the compound (I) can also be produced by subjecting the aniline 16 and an aryl acid chloride to a Friedel-Crafts reaction to yield the ketone 17, converting the aniline derivative into a diazonium salt, reducing the diazonium salt with tin chloride, and closing the ring of the resulting compound.
  • Lewis acids for use in the Friedel-Crafts reaction for the production of the ketone 17 include, for example, aluminium(III) chloride and ethylaluminium dichloride.
  • Solvents for use herein are preferably halogen-containing solvents such as methylene chloride or chloroform.
  • a reaction temperature is generally from -50°C to the reflux temperature of the solvent.
  • the ketone 17 can be converted into the diazonium salt by allowing the ketone 17 to react with sodium nitrite in the presence of an acid.
  • Reaction solvents for use herein include, for example, alcohol solvents such as methanol or ethanol, as well as hydrochloric acid, sulfuric acid, and acetic acid.
  • a reaction temperature is generally from 0°C to room temperature.
  • the diazonium salt can be reduced and the indazole ring can be closed by allowing the diazonium salt to react with tin(II) chloride in the presence of an acid.
  • Reaction solvents for use herein include, for example, alcohol solvents such as methanol or ethanol, as well as hydrochloric acid, sulfuric acid, and acetic acid.
  • a reaction temperature is generally from 0°C to room temperature.
  • the compound (I)-a can be produced by converting the ortho-halogenofluorobenzene 18 into a lithium aryl, allowing the lithium aryl to react with an aryl aldehyde to yield the alcohol 19, oxidizing the alcohol 19 into the ketone 20, converting the acetal into the ester, treating the ester with hydrazine into the indazole 22, hydrolyzing the indazole 22 into the carboxylic acid 23, and amidating the carboxylic acid 23.
  • Alkyllithiums for converting the ortho-halogenofluorobenzene 18 into the lithium aryl include, for example, n -butyllithium, sec -butyllithium, tert -butyllithium, and phenyllithium. Where necessary, an additive such as N,N,N',N' -tetramethylethylenediamine or hexamethylphosphoramide can be added. Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and preferred examples thereof are ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene and toluene. A reaction temperature is from -78°C to room temperature.
  • Oxidizing agents for oxidizing the alcohol 19 include, for example, manganese dioxide, sulfur trioxide-pyridine complex, N-methylmorpholine-N-oxide, and chromic acid oxidizing agents.
  • the oxidation can also be performed by Swern oxidation or Moffat oxidation.
  • Solvents for use herein can be any solvents that are not involved in the reaction and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from -78°C to the reflux temperature of the solvent.
  • the ester 21 can be produced by treating with an acid into the aldehyde, oxidizing the aldehyde into the carboxylic acid, and esterifying the carboxylic acid.
  • Acids for use in conversion into the aldehyde include, but are not specifically limited to, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, hydrochloric acid, and sulfuric acid.
  • Solvents for use herein can be any solvents that are not involved in the reaction and include, for example, alcohol solvents such as methanol or ethanol, as well as acetone, and tetrahydrofuran.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • Oxidizing agents for oxidizing the aldehyde into the carboxylic acid include, for example, Jones reagents and sodium chlorite.
  • Solvents for use herein can be any solvents that are not involved in the reaction and include, for example, halogen-containing solvents such as methylene chloride or chloroform, as well as ethyl acetate, dimethylformamide, and dimethyl sulfoxide.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the carboxylic acid can be converted into the ester, for example, by allowing the carboxylic acid with an alkyl iodide in the presence of a base or to react with diazomethane.
  • bases for use herein include sodium hydride, potassium carbonate, and potassium tert -butoxide.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the cyclization of the ester 21 with hydrazine monohydrate can be performed in the absence of, or in the presence of, a solvent.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, alcohol solvents such as methanol, ethanol or propanol, as well as pyridine, dimethyl sulfoxide, benzene, and toluene.
  • the amount of the hydrazine monohydrate is from 2 to 20 equivalents to the raw material.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the ester 22 can be easily hydrolyzed by using, for example, aqueous sodium hydroxide or aqueous potassium hydroxide.
  • Solvents for use herein can be any solvents that are not involved to the reaction and include, for example, alcohol solvents such as methanol or ethanol, as well as tetrahydrofuran, dioxane, and other ether solvents.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the carboxylic acid 23 can be amidated by treating with an amine and a condensing agent.
  • condensing agents include, for example, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.
  • 1-hydroxybenzotriazole and/or N-hydroxysuccinimide can be added.
  • Solvents for use herein can be any solvents that are not involved in the reaction and include, for example, halogen-containing solvents such as methylene chloride or chloroform, ether solvents such as ether or tetrahydrofuran, as well as ethyl acetate, dimethylformamide, and toluene.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the alcohol 19 can also be produced by converting the ortho-halogenofluorobenzene 18 into a lithium aryl by the procedure of Production Process 12, allowing the lithium aryl to react with a formylation agent to yield the aldehyde 24, and allowing the aldehyde 24 to react with a metal aryl or metal halogenoaryl.
  • Formylation agents for formylation of the lithium aryl prepared from the ortho-halogenofluorobenzene 18 by the procedure of Production Process 12 include, for example, dimethylformamide, N -formylpiperidine, and methylphenylformamide.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene and toluene.
  • a reaction temperature is from -78°C to room temperature.
  • the metal aryl or metal halogenoaryl for the reaction with the aldehyde 24 can be easily prepared by the procedure of Production Process 2.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene and toluene.
  • a reaction temperature is from -78°C to room temperature.
  • the carboxylic acid 23 can also be produced by treating the fluorobenzene 25 with, for example, an alkyllithium or lithium amide to yield an lithium aryl, allowing the lithium aryl to react with an aryl aldehyde to yield the alcohol 26, oxidizing the alcohol 26 into the ketone 27, treating the ketone 27 with hydrazine to yield the indazole 28, and hydrolyzing the nitrile.
  • the alkyllithium for converting the fluorobenzene 25 into the lithium aryl includes, for example, n -butyllithium, sec -butyllithium, tert -butyllithium, and phenyllithium. Where necessary, an additive such as N,N,N',N' -tetramethylethylenediamine or hexamethylphosphoramide can be added.
  • the lithium amide includes, for example, lithium diisopropylamide, and lithium 2,2,6,6-tetramethylpiperidide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and preferred examples thereof are ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene and toluene.
  • a reaction temperature is from -78°C to room temperature.
  • the compound 28 can be produced by oxidizing the alcohol and closing the indazole ring with the use of hydrazine monohydrate by the procedure of Production Process 12.
  • the nitrile moiety of the compound 28 can be hydrolyzed by using an acid or a base.
  • Such acids include, for example, hydrochloric acid and hydrous sulfuric acid.
  • the reaction can be performed in the absence of, or in the presence of a solvent.
  • solvents include, for example, alcohol solvents such as methanol, ethanol or propanol, as well as acetic acid.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the base includes, for example, sodium hydroxide and potassium hydroxide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, of which alcohol solvents such as methanol, ethanol or propanol are preferred.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the compound (I)-b can be prepared by protecting the 1-position of the ester 22 produced in Production Process 12 to yield the compound 29, reducing the compound 29 into the alcohol 30, converting the alcohol 30 into a sulfonate or halogen 31, converting the same into the cyano compound 32 and then into the carboxylic acid 33, and amidating the carboxylic acid 33.
  • Protecting groups for protecting the 1-position of the ester 22 include, for example, tert -butyloxycarbonyl group, p-toluenesulfonyl group, triphenylmethyl group, and methoxymethyl group.
  • the tert -butyloxycarbonyl group and p -toluenesulfonyl group can be introduced by allowing the ester 22 to react with di-tert-butyl dicarbonate or p-toluenesulfonyl chloride in the presence of a base.
  • bases are not specifically limited, and preferred examples are triethylamine and 4- N,N -dimethylaminopyridine.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, , halogenated hydrocarbons such as dichloromethane or chloroform, as well as pyridine, ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the triphenylmethyl group and methoxymethyl group can be introduced by allowing the ester 22 to react with chlorotriphenylmethane or chloromethyl methyl ether in the presence of a base.
  • Such bases are not specifically limited, and preferred examples are sodium hydride, potassium tert -butoxide, lithium diisopropylamide, potassium carbonate, and sodium hydroxide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as pyridine, ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from -20°C to the reflux temperature of the solvent.
  • Reducing agents for reducing the ester moiety of the compound 29 include, for example, di-iso-butylaluminium hydride, lithium aluminium hydride, and lithium borohydride.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene and toluene.
  • a reaction temperature is generally from -20°C to the reflux temperature of the solvent.
  • the alcohol 30 can be converted into the sulfonate by allowing the alcohol 30 to react with a sulfonyl chloride in the presence of a base.
  • sulfonyl chloride examples include methanesulfonyl chloride, and p-toluenesulfonyl chloride.
  • Bases for use herein are not specifically limited and include, for example, triethylamine, 4-dimethylaminopyridine, and sodium hydride.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, halogen-containing solvents such as methylene chloride or chloroform, as well as pyridine, benzene, toluene, and dimethylformamide.
  • a reaction temperature is from -20°C to the reflux temperature of the solvent.
  • a chloride By performing the reaction in dichloromethane in the presence of triethylamine for a long time, a chloride can be obtained.
  • the sulfonate and chloride can be converted into an iodide by allowing the same to react with about 1.1 equivalent of sodium iodide in acetone at room temperature.
  • the nitrile 32 can be obtained by allowing the sulfonate or halide 31 to react with sodium cyanide or potassium cyanide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and include, for example, alcohol solvents such as methanol or ethanol, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as dimethylformamide, and dimethyl sulfoxide.
  • a reaction temperature is from-20°C to the reflux temperature of the solvent.
  • the nitrile 32 can be hydrolyzed by using an acid. Such acids include, for example, hydrochloric acid and hydrous sulfuric acid.
  • the reaction can be performed in the absence of, or in the presence of a solvent.
  • Such solvents include, for example, alcohol solvents such as methanol, ethanol or propanol, as well as acetic acid.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent. In this reaction, the protecting group is removed concurrently.
  • the compound 30 can also be produced by reducing the ester 22 having a non-protected 1-position produced in Production Process 12, and protecting the 1-position.
  • the ester 22 is reduced by the procedure of Production Process 15 to thereby yield the alcohol 34.
  • a protecting group is introduced into the 1-position of the alcohol 34 by the procedure of Production Process 15 to thereby.yield the compound 30.
  • the compound (I)-c can be produced by oxidizing the alcohol 30 produced in Production Process 15 into the aldehyde 35, subjecting the aldehyde 35 to a Wittig reaction to yield the ester 36, converting the ester 36 into the carboxylic acid 37, and amidating the carboxylic acid 37.
  • Oxidizing agents for oxidizing the alcohol 30 include, for example, manganese dioxide, sulfur trioxide-pyridine complex, N-methylmorpholine-N-oxide, and chromic acid oxidizing agents.
  • the oxidation can also be performed by Swern oxidation or Moffat oxidation.
  • Solvents for use herein can be any solvents that are not involved in the reaction and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from -78°C to the reflux temperature of the solvent.
  • Reagents for the Wittig reaction of the aldehyde 30 include, for example, triethyl phosphonoacetate, ethyl diphenylphosphonoacetate, and (carbethoxymethyl)triphenylphosphonium bromide.
  • Bases for use herein include, but are not specifically limited to, sodium hydride, sodium hydrogencarbonate, potassium carbonate, sodium hydroxide, potassium tert -butoxide, and benzyltrimethylammonium hydroxide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, halogenated hydrocarbons such as dichloromethane or chloroform, as well as ethyl acetate, acetonitrile, toluene, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from 0°C to room temperature.
  • the compound (I)-d can be produced by hydrogenating the carboxylic acid 37 produced in Production Process 17, and amidating the resulting compound.
  • Hydrogenation reagents for the olefin moiety of the carboxylic acid 37 include, but are not specifically limited to, palladium-carbon, platinum oxide, and palladium hydroxide-carbon.
  • the pressure of hydrogen is from 1 to 5 atom.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform, as well as ethyl acetate, acetonitrile, toluene, and dimethylformamide.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the compound (I)-d can be produced by amidating the carboxylic acid 38 according to the procedure of Production Process 12.
  • the compound (I)-e can be produced by halogenating the 3-position of the compound 39 into the compound 40, protecting the 1-position of the compound 40 to yield the compound 41, subjecting the compound 41 to Suzuki coupling with an arylboronic acid to yield the compound 42, reducing the compound 42 into the aniline 43, amidating the aniline 43 into the compound 44, and deprotecting the 1-position.
  • Halogenation reagents for the 3-position of the compound 39 include, for example, N -bromosuccinimide, N -iodosuccinimide, N -chlorosuccinimide, and bromine.
  • a radical reaction initiator such as 2,2'-azobisisobutyronitrile and benzoyl peroxide can be added.
  • the amount of the halogenation reagent is from 1.05 to 1.2 equivalents to the raw material.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • Protecting groups for the 1-position of the compound 40 include, for example, tert -butyloxycarbonyl group, p -toluenesulfonyl group, and triphenylmethyl group.
  • the tert -butyloxycarbonyl group and p -toluenesulfonyl group can be introduced by allowing the compound 40 to react with di-tert-butyl dicarbonate or p-toluenesulfonyl chloride in the presence of a base.
  • bases are not specifically limited, and preferred examples thereof are triethylamine and 4- N,N -dimethylaminopyridine.
  • Solvents for use herein are not specifically limited, as long as they are inert in the reaction, and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, halogenated hydrocarbons such as dichloromethane or chloroform, as well as pyridine, ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the triphenylmethyl group can be introduced by allowing the compound 40 to react with chlorotriphenylmethane in the presence of a base.
  • Such bases include, but are not specifically limited to, sodium hydride, potassium tert-butoxide, lithium diisopropylamide, potassium carbonate, and sodium hydroxide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is from -20°C to the reflux temperature of the solvent.
  • arylboronic acids for use in Suzuki coupling of the compound 41 those commercially available will be purchased, and those not commercially available can be easily prepared according to the procedure of Production Process 3.
  • the amount of the arylboronic acid is from 1 to 3 equivalents to the raw material.
  • Catalysts for use herein include, for example, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), and tetrakis(triphenylphosphine)palladium(0).
  • the amount of the catalyst is about 5% by mole relative to the raw material. Where necessary, a phosphine ligand in an amount of two times by mole that of the catalyst can be added.
  • Such phosphine ligands include, for example, tri- tert -butylphosphine, 2-(di- tert -butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, and triphenylphosphine.
  • bases for use herein are sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and potassium fluoride.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, dimethylformamide, N -methylpyrrolidone, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, and toluene.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the nitro group of the compound 42 is reduced, for example, by hydrogenation by catalysis of palladium-carbon, palladium hydroxide-carbon, platinum oxide, or Raney's nickel, as well as reduction with tin(II) chloride, and reduction with iron-ammonium chloride.
  • Solvents for use in the hydrogenation are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, alcohol solvents such as methanol or ethanol, halogen-containing solvents such as methylene chloride or chloroform, ether solvents such as tetrahydrofuran or diethyl ether, as well as ethyl acetate, dimethylformamide, and toluene.
  • the amount of the hydrogenation catalyst is from 5% to 20% by weight relative to the raw material.
  • the pressure of hydrogen is generally from 1 to 5 atom.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • Solvents for use in the reduction with tin(II) chloride include, for example, alcohol solvents such as methanol or ethanol, halogenated hydrocarbon solvents such as methylene chloride or chloroform, as well as dimethylformamide, N -methylpyrrolidone, and toluene.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • Solvents for use in the reduction with iron-ammonium chloride are preferably alcohol solvents such as aqueous methanol or aqueous ethanol.
  • the amount of iron is from 3 to 10 equivalents to the raw material.
  • the amount of the ammonium chloride is from 10% to 20% by weight relative to the raw material.
  • a reaction temperature is generally the reflux temperature of the solvent.
  • the aniline 43 can be amidated by treating with a carboxylic acid and a condensing agent.
  • condensing agents include, for example, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.
  • 1-hydroxybenzotriazole and/or N-hydroxysuccinimide can be added.
  • Solvents for use herein can be any solvents that are not involved in the reaction and include, for example, halogen-containing solvents such as methylene chloride or chloroform, ether solvents such as ether or tetrahydrofuran, as well as ethyl acetate, dimethylformamide, and toluene.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the aniline 43 can also be amidated by allowing the aniline 43 to react with an acid chloride in the presence of a base.
  • bases include, but are not specifically limited to, triethylamine, diisopropylethylamine, and pyridine.
  • Solvents for use herein can be any solvents that are not involved in the reaction and include, for example, halogen-containing solvents such as methylene chloride or chloroform, ether solvents such as ether or tetrahydrofuran, as well as ethyl acetate, and toluene.
  • a reaction temperature is generally from -78°C to the reflux temperature of the solvent.
  • the tert-butyloxycarbonyl group and triphenylmethyl group as the protecting group of the amide 44 can be easily deprotected or removed by using an acid.
  • Such acids include, for example, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.
  • a radical scavenger such as thiophenol and tri- iso -propylsilane can be added.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, alcohol solvents such as methanol or ethanol, as well as anisole.
  • a reaction temperature is generally from -20°C to the reflux temperature of the solvent.
  • the tert -butyloxycarbonyl group and p-toluenesulfonyl group as the protecting agent can be easily deprotected by using a base.
  • Such bases include, but are not specifically limited to, aqueous sodium hydroxide and aqueous potassium hydroxide.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, alcohol solvents such as methanol or ethanol, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane.
  • a reaction temperature is from room temperature to the reflux temperature of the solvent.
  • the compound (I)-e can also be produced by deprotecting or removing, by the procedure of Production Process 19, the protecting group of the aniline 43 produced in Production Process 19 to yield the compound 45, and amidating the compound 45 according to the amidation procedure using a condensing agent as in Production Process 19.
  • the aniline 45 can also be produced by subjecting the nitro derivative 40 having a non-protected 1-position produced in Production Process 19 to Stille coupling to yield the compound 46, and reducing the nitro group.
  • aryltrialkyltins for use in the Stille coupling of the nitro derivative 40 those commercially available will be purchased, and those not commercially available can be easily prepared according to the procedure of Production Process 5.
  • the amount of the aryltrialkyltin is from 1 to 3 equivalents to the raw material.
  • Catalysts for use herein include, for example, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), and tetrakis(triphenylphosphine)palladium(0).
  • the amount of the catalyst is about 5% by mole relative to the raw material.
  • a phosphine ligand in an amount of two times by mole that of the catalyst can be added.
  • Such phosphine ligands include, for example, tri- tert -butylphosphine, 2-(di- tert -butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, and triphenylphosphine.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, dimethylformamide, N -methylpyrrolidone, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, toluene, and xylenes.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the compound 42 can also be produced by introducing, according to the procedure of Production Process 19, a protecting group into the compound 46 produced in Production Process 21.
  • the compound (I)-f can be produced by alkylating the amide 44 produced in Production Process 19 to yield the N -alkylamide 47, and deprotecting the N -alkylamide 47.
  • the amide 44 can be alkylated by allowing the amide 44 to react with a halogenoalkyl in the presence of a base.
  • bases include, but are not specifically limited to, sodium hydride, potassium carbonate, potassium tert -butoxide, and potassium hydroxide.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, ether solvents such as ether, tetrahydrofuran or dioxane, as well as dimethylformamide, dimethyl sulfoxide, and toluene.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the compound (I)-g can be produced by converting the aniline 43 produced in Production Process 19 into the sulfonamide 48, and deprotecting the sulfonamide 48.
  • the aniline 43 can be converted into the sulfonamide by allowing the aniline 43 to react with a sulfonyl chloride in the presence of a base.
  • bases include, but are not specifically limited to, triethylamine, 4-dimethylaminopyridine, potassium carbonate, sodium hydride, and pyridine.
  • the amount of the sulfonyl chloride is from 1.1 to 1.5 equivalents to the raw material.
  • Reaction solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, ether solvents such as ether, tetrahydrofuran or dioxane, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, toluene, and dimethylformamide. Among them, ether, tetrahydrofuran, dioxane, and other ether solvents are preferred.
  • a reaction temperature is generally from 0°C to room temperature.
  • the compound (I)-g can also be produced by converting the aniline 45 having a non-protected 1-position produced in Production Process 21 into a sulfonamide according to the procedure of Production Process 24.
  • the compound (I)-h can be produced by alkylating the sulfonamide 48 produced in Production Process 24, and deprotecting the resulting compound.
  • the sulfonamide 48 can be alkylated by allowing the sulfonamide 48 to react with a halogenoalkyl in the presence of a base.
  • bases include, but are not specifically limited to, sodium hydride, potassium carbonate, potassium tert -butoxide, and triethylamine.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, ether solvents such as ether, tetrahydrofuran or dioxane, as well as dimethylformamide, dimethyl sulfoxide, and toluene.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the compound (I)-i can be produced by subjecting the indazole 50 to halogenation and introduction of a protecting group according to the procedure of Production Process 19 to yield the compound 52, allowing the compound 52 to react with chlorosulfuric acid to yield sulfonyl chloride 53, converting the sulfonyl chloride 53 into the sulfonamide 54, subjecting the sulfonamide 54 to Suzuki coupling to yield the compound 55, and deprotecting the compound 55.
  • the sulfonyl chloride 53 can be obtained by allowing the halogenated compound 52 to react with 1 to 2 equivalents of chlorosulfuric acid.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, halogen-containing solvents such as methylene chloride or chloroform.
  • a reaction temperature is generally from 0°C to room temperature.
  • the sulfonyl chloride 53 can be sulfonamidated by allowing the sulfonyl chloride 53 to react with an amine in the presence of a base. An excess amount of the amine can serve as the base.
  • triethylamine, 4-dimethylaminopyridine, potassium carbonate, and sodium hydride can be added as the base.
  • Reaction solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, ether solvents such as ether, tetrahydrofuran or dioxane, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, toluene, and dimethylformamide.
  • a reaction temperature is generally from 0°C to room temperature.
  • the sulfonamide 54 is subjected to Suzuki coupling with an arylboronic acid according to the procedure of Production Process 19 to thereby yield the compound 55.
  • the compound 55 is then deprotected according to the procedure of Production Process 19 to thereby yield the compound (I)-i.
  • the compound (I)-j can be produced by converting the halide or sulfonate produced in Production Process 15 into an azide, reducing the azide into the amine 57, deprotecting the amine 57 to yield the compound 58, and amidating the compound 58.
  • the azide 56 can be obtained by allowing the compound 31 to react with sodium azide or potassium azide.
  • Reaction solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, alcohol solvents such as methanol or ethanol, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from -20°C to the reflux temperature of the solvent.
  • the azide 56 can be reduced, for example, by hydrogenation by catalysis of palladium-calcium carbonate, palladium-carbon, palladium hydroxide-carbon, platinum oxide, and Raney nickel.
  • Solvents for use in the hydrogenation are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, alcohol solvents such as methanol or ethanol, halogen-containing solvents such as methylene chloride or chloroform, ether solvents such as tetrahydrofuran or diethyl ether, as well as ethyl acetate, dimethylformamide, and toluene.
  • the amount of the hydrogenation catalyst is from 5% to 20% by weight relative to the raw material.
  • the pressure of hydrogen is generally normal pressure (atmospheric pressure) but can be increased up to 5 atm.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the 1-position of the amine 57 is deprotected according to the procedure of Production Process 3 to thereby yield the compound 58.
  • the compound 58 is amidated according to the procedure of Production Process 19 using a condensing agent to thereby yield the compound (I)-j.
  • the compound 58 obtained in Production Process 28 can also be produced by reducing the nitrile 28 produced in Production Process 14.
  • Reducing agents for use herein include, for example, sodium borohydride, lithium aluminium hydride, and aluminium hydride. Where necessary, an additive such as aluminium trichloride, boron trifluoride, cobalt chloride, and Raney nickel can be added.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, alcohol solvents such as methanol or ethanol, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane.
  • a reaction temperature is from -78°C to the reflux temperature of the solvent.
  • the compound (I)-k can be produced by converting the sulfonate or halide 31 obtained in Production Process 15 into the amine 59, and deprotecting the amine 59.
  • the sulfonate or halide 31 can be aminated to react with an amine in the presence of a base. An excess amount of the amine can serve as the base.
  • a base such as sodium hydride, potassium carbonate, and potassium tert -butoxide can be added.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, alcohol solvents such as methanol or ethanol, halogen-containing solvents such as methylene chloride or chloroform, ether solvents such as tetrahydrofuran or diethyl ether, as well as ethyl acetate, dimethylformamide, dimethyl sulfoxide, and toluene.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the compound (I)-1 can be produced by allowing the sulfonate or halide 31 obtained in Production Process 15 to react with an alcohol in the presence of a base to thereby yield the ether 60, and deprotecting the ether 60.
  • Bases for use in the etherification of the sulfonate or halide 31 include, but are not specifically limited to, sodium hydride, potassium carbonate, potassium tert -butoxide, and silver(I) oxide.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, halogen-containing solvents such as methylene chloride or chloroform, ether solvents such as tetrahydrofuran or diethyl ether, as well as ethyl acetate, dimethylformamide, dimethyl sulfoxide, and toluene.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the compound (I)-m can be produced by subjecting the alcohol 30 obtained in Production Process 15 and an aryl alcohol to Mitsunobu reaction to thereby yield the aryl ether 61, and deprotecting the aryl ether 61.
  • the compound 61 can be produced, for example, by allowing the alcohol 30 to react with the aryl alcohol in the presence of triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate.
  • Solvents for use herein are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, halogen-containing hydrocarbons such as methylene chloride or chloroform, ether solvents such as tetrahydrofuran, diethyl ether or dioxane, as well as ethyl acetate, dimethylformamide, and toluene.
  • a reaction temperature is generally from 0°C to room temperature.
  • the compound (I)-n can be produced by allowing the aniline 43 obtained in Production Process 19 to react with an isocyanate to yield the urea 62, and deprotecting the urea 62.
  • Solvents for use in the conversion of the aniline 43 into the urea are not specifically limited, as long as they do not adversely affect the reaction, and include, for example, halogen-containing solvents such as methylene chloride or chloroform, ether solvents such as tetrahydrofuran or diethyl ether, as well as ethyl acetate, dimethylformamide, dimethyl sulfoxide, and toluene.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • the compound (I)-o can be produced by allowing the aldehyde 35 obtained in Production Process 17 to react with an alkyllithium, a Grignard reagent, a metal aryl, or a metal halogenoaryl to yield the alcohol 63, oxidizing the alcohol 63 into the ketone 64, and deprotecting the ketone 64.
  • the alkyllithium for the reaction of the aldehyde 35 is commercially available.
  • the Grignard reagent can be prepared by using an alkyl halide and magnesium.
  • metal aryls or metal halogenoaryls for use herein those commercially available will be purchased, and those not commercially available can be easily prepared according to the procedure of Production Process 3.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene, and toluene.
  • a reaction temperature is from -78°C to room temperature.
  • Oxidizing agents for oxidizing the alcohol 63 include, for example, manganese dioxide, sulfur trioxide-pyridine complex, N-methylmorpholine-N-oxide, and chromic acid oxidizing agents. The oxidation can also be performed by Swern oxidation or Moffat oxidation.
  • Solvents for use herein can be any solvents that are not involved in the reaction and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, as well as ethyl acetate, acetonitrile, dimethyl sulfoxide, and dimethylformamide.
  • a reaction temperature is generally from -78°C to the reflux temperature of the solvent.
  • the compound 27 obtained in Production Process 14 can also be produced by treating the fluorobenzene 65 with, for example, lithium amide to yield a lithium aryl, allowing the lithium aryl to react with an aryl aldehyde to yield the alcohol 66, oxidizing the alcohol 66 into a ketone, and replacing T 2 a with cyano group.
  • Lithium amides for converting the fluorobenzene 65 into the lithium aryl include, for example, lithium diisopropylamide, and lithium 2,2,6,6-tetramethylpiperidide.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, and preferred examples thereof are ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene, and toluene.
  • a reaction temperature is from -78°C to room temperature.
  • Reagents for converting the compound 67 into the nitrile 27 include zinc cyanide, lithium cyanide, sodium cyanide, or potassium cyanide in combination with a transition metal catalyst such as tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium, and palladium diacetate.
  • the reaction may be performed in the presence of a catalytic amount of copper iodide or a phosphine ligand such as triphenylphosphine and 1,1'-bis(diphenylphosphino)ferrocene.
  • solvents for use herein are dimethylformamide, N-methylpyrrolidone, propionitrile, and acetonitrile.
  • a reaction temperature is preferably within a range from 80°C to 150°C.
  • the nitrile 27 can also be produced by allowing the compound 67 to react with copper cyanide in a solvent such as dimethylformamide or N-pyrrolidone at a temperature within a range from 140°C to 200°C.
  • the carboxylic acid 23 obtained in Production Process 12 can also be produced by treating the compound 67 obtained in Production Process 35 with hydrazine to yield the indazole 68, converting the indazole 68 into a lithium aryl with the use of an alkyl lithium, and allowing the lithium aryl to react with carbon dioxide.
  • the alkyllithium for converting the indazole 68 into the lithium aryl includes, for example, n -butyllithium, sec -butyllithium, tert -butyllithium, and phenyllithium. Where necessary, an additive such as N,N,N',N' -tetramethylethylenediamine or hexamethylphosphoramide can be added.
  • reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction, and preferred examples thereof are ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as benzene, and toluene.
  • a reaction temperature is from -78°C to room temperature.
  • the aniline 43 obtained in Production Process 19 can also be produced by protecting the 1-position of the carboxylic acid 23 obtained in Production Process 12 to yield the compound 69, subjecting the compound 69 to Curtius rearrangement to yield the carbamate 70, and deprotecting the carbamate.
  • the compound 69 By introducing a protecting group into the 1-position according to the procedure of Production Process 15, the compound 69 can be produced.
  • the compound 69 can be subjected to Curtius rearrangement by treating the compound 69 with, for example, diphenylphosphoryl azide and an amine such as triethylamine or diisopropylethylamine to yield an isocyanate, and allowing the isocyanate to react with an alcohol, or by treating the compound 69 with, for example, thionyl chloride or oxalyl chloride to yield an acid chloride, treating the acid chloride with lithium azide, sodium azide or potassium azide to yield an isocyanate, and allowing the isocyanate to react with an alcohol.
  • the alcohol for use herein is not specifically limited, of which benzyl alcohol and tert-butanol are especially preferred.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, toluene, benzene, tetrahydrofuran, and dioxane.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • a tert -butyloxycarbonyl group as the protecting group of the carbamate 70 can be easily deprotected or removed by using an acid.
  • Such acids include, for example, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.
  • a radical scavenger such as thiophenol or tri- iso -propylsilane
  • Solvents for use herein are not specifically limited, as long as they are inert in the reaction, and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform, as well as anisole.
  • a benzyloxycarbonyl group as the protecting group can be easily deprotected or removed by hydrogenation.
  • Reagents for use in the hydrogenation include, but are not specifically limited to, palladium-carbon, platinum oxide, and palladium hydroxide-carbon.
  • the pressure of hydrogen is from 1 to 5 atm.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, ether solvents such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, halogenated hydrocarbons such as dichloromethane or chloroform, as well as ethyl acetate, acetonitrile, toluene, and dimethylformamide.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the aniline 43 obtained in Production Process 19 can also be produced by protecting the 1-position of the compound 68 obtained in Production Process 36 to yield the compound 71, and then aminating T 2 .
  • Palladium catalysts for use in amination of the compound 71 include, for example, tris(dibenzylideneacetone)dipalladium, and palladium diacetate.
  • Phosphine ligands for use herein include, for example, 2,2'-bis(diphenylphosphino)-1,1'-naphthyl, 1,1'-bis(diphenylphosphino)ferrocene, and tri( tert -butyl)phosphine.
  • Bases for use herein include, for example, sodium tert -butoxide, potassium tert-butoxide, and cesium carbonate.
  • An ammonia equivalent for use herein is not specifically limited and is preferably benzophenoneimine.
  • Acids for use in hydrolysis of the resulting imine derivative include, but are not specifically limited to, diluted hydrochloric acid and diluted sulfuric acid.
  • Solvents for use in the reaction are not specifically limited, as long as they are inert to the reaction, and include, for example, toluene, tetrahydrofuran, dioxane, and dimethoxyethane.
  • a reaction temperature is generally from room temperature to 120°C.
  • the compound (I)-e can also be produced by combining, with a resin, the 1-position of the compound 40 obtained in Production Process 19 to yield the compound 72, subjecting the product to Suzuki coupling with an arylboronic acid to yield the compound 73, reducing the product into the aniline 74, amidating the product into the compound 75, and then exciding the target compound from the resin using an acid.
  • Advantages of the synthesis using a resin are that a multitude of a target compound can be synthetically prepared at once, that a purification procedure in each step is not required, as an excess reagent can be removed by washing, and that the resin itself serves as a protecting group.
  • Such bases include, but are not specifically limited to, triethylamine, diisopropylethylamine, 4- N,N -dimethylaminopyridine, sodium hydride, potassium tert -butoxide, and potassium carbonate.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and can hold affinity for the resin, and include, for example, ether solvents tetrahydrofuran or dioxane, as well as dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, ethyl acetate, and acetonitrile.
  • a reaction temperature is generally from 0°C to the reflux temperature of the solvent.
  • arylboronic acids for use in Suzuki coupling of the compound 72 those commercially available will be purchased, and those not commercially available can be easily prepared according to the procedure of Production Process 3.
  • the arylboronic acid is used in excess.
  • Catalysts for use herein include, for example, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), and tetrakis(triphenylphosphine)palladium(0).
  • the amount of the catalyst is about 5% by mole relative to the arylboronic acid. Where necessary, a phosphine ligand in an amount of two times by mole that of the catalyst can be added.
  • Such phosphine ligands include, for example, tri- tert -butylphosphine, 2-(di- tert -butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, and triphenylphosphine.
  • Bases for use herein include, for example, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and potassium fluoride.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and can hold affinity for the resin, and include, for example, dimethylformamide, N -methylpyrrolidone, tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the nitro group of the compound 73 can be reduced, for example, by reduction with tin(II) chloride or reduction with iron-ammonium chloride.
  • Solvents for use in the reduction with tin(II) chloride include, for example, alcohol solvents such as methanol or ethanol, dimethylformamide, and N -methylpyrrolidone.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • Solvents for use in the reduction with iron-ammonium chloride are preferably alcohol solvents such as aqueous methanol or aqueous ethanol.
  • the amount of iron is from 3 to 10 equivalents to the raw material.
  • the amount of the ammonium chloride is from 10% to 20% by weight relative to the raw material.
  • a reaction temperature is generally the reflux temperature of the solvent.
  • the aniline 74 can be amidated by treating with a carboxylic acid and a condensing agent.
  • Such condensing agents include, for example, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.
  • 1-hydroxybenzotriazole and/or N-hydroxysuccinimide can be added.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction and can hold affinity for the resin, and include, for example, ether solvents such as tetrahydrofuran or dioxane, as well as dimethylformamide, N-methylpyrrolidone, and ethyl acetate.
  • a reaction temperature is generally from room temperature to the reflux temperature of the solvent.
  • the compound (I)-e can be easily excided from the resin using an acid.
  • acids include, for example, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.
  • a radical scavenger such as thiophenol or tri- iso -propylsilane can be added.
  • Solvents for use herein are not specifically limited, as long as they are inert to the reaction, and include, for example, halogenated hydrocarbons such as dichloromethane or chloroform.
  • a reaction temperature is from room temperature to the reflux temperature of the solvent.
  • the compound (I)-g can also be produced by converting the aniline 74 obtained in Production Process 39 into the sulfonamide 76, and then exciding the target compound from the resin using an acid.
  • the aniline 74 can be converted into the sulfonamide by allowing it to react with a sulfonyl chloride in the presence of a base.
  • bases include, but are not specifically limited to, triethylamine, 4-dimethylaminopyridine, potassium carbonate, and sodium hydride.
  • the amount of the base is from 0.9 to 1.1 equivalents to the sulfonyl chloride.
  • Reaction solvents for use herein are not specifically limited, as long as they are inert to the reaction and can hold affinity for the resin, and include, for example, ether solvents such as tetrahydrofuran or dioxane, as well as dimethyl sulfoxide, N -methylpyrrolidone, dimethylformamide, ethyl acetate, and acetonitrile. Among them, ether solvents such as tetrahydrofuran or dioxane are preferred.
  • a reaction temperature is generally from 0°C to room temperature.
  • Material compounds for use in the production of the compounds of the present invention can be in the form of salts and/or hydrates and are not specifically limited as long as they do not adversely affect the reactions.
  • the compounds (I) according to the present invention can be converted into acceptable salts of the above-mentioned compound (I) according to a conventional procedure.
  • Various isomers such as geometrical isomers, optical isomers due to an asymmetric carbon, stereoisomers, and tautomers obtained as the compounds (I) according to the present invention can be purified and isolated according to a conventional separation means.
  • Such separation means include, for example, recrystallization, diastereomeric salt method, enzymatic resolution, and a variety of chromatography such as thin layer chromatography, column chromatography or gas chromatography.
  • salts are hydrohalides such as hydrofluorides, hydrochlorides, hydrobromides or hydroiodides; salts of inorganic acids, such as sulfates, nitrates, perchlorates, phosphates, carbonates or bicarbonates; salts of organic carboxylic acids, such as acetates, trifluoroacetates, oxalates, maleates, tartrates, fumarates or citrates; salts of organic sulfonic acids, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates or camphorsulfonates; salts of amino acids, such as aspartates or glutamates;
  • the compounds represented by the formula (I) according to the present invention, a salt thereof or a hydrate of them can be formulated into pharmaceutical preparations according to a conventional procedure.
  • Preferred dosage forms are tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalants, suppositories, injections, ointments, ophthalmic ointments, eye drops, nasal drops, ear drops, cataplasms, and lotions.
  • fillers In the formulation, generally used fillers, binders, disintegrators, lubricants, coloring agents, and flavoring agents, as well as stabilizers, emulsifiers, absorbefacients, surfactants, pH adjusting agents, antiseptics, and antioxidants according to necessity can be used. They can be formulated according to a conventional procedure using components generally used as raw materials for pharmaceutical preparations.
  • Such components include (1) animal or vegetable oils such as soybean oil, beef tallow or synthetic glycerides; (2) hydrocarbons such as liquid paraffins, squalane or solid paraffins; (3) ester oils such as octyldodecyl myristate or isopropyl myristate; (4) higher alcohols such as cetostearyl alcohol or behenyl alcohol; (5) silicon resins; (6) silicon oils; (7) surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oils or polyoxyethylene-polyoxypropylene block copolymers; (8) water-soluble polymers such as hydroxyethyl cellulose, poly(acrylic acid)s, carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidone or methylcellulose; (9) lower alcohols such as ethanol or isopropano
  • the fillers include, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide; 2) the binders include, for example, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, gum tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymers, meglumine, calcium citrate, dextrin, and pectin; 3) the disintegrators include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin, pectin, and carboxymethylcellulose calcium; 4) the lubricants include, for example, magnesium stearate, talc, polyethylene glycol, silica, and hardened vegetable oils; 5) the coloring
  • the compound according to the present invention or the salt thereof is compounded with a filler, and if necessary, a binder, disintegrator, lubricant, coloring agent, flavoring agent, and other components, and the resulting mixture is formulated according to a conventional procedure into a powder, fine granules, granules, tablet, coated tablet, capsule, etc.
  • the tablets and granules can be appropriately coated with, for example, sugar or gelatin, or other according to necessity.
  • Liquid formulations such as syrups, injection preparations or eye droppers can be prepared in a conventional method, by adding a pH adjusting agents, solubilizer, and isotonizing agent, and if necessary, a solubilizing agent, stabilizer, buffer, suspending agent, antioxidant, and other components.
  • the liquid formulations can also be formed into freeze-dried products.
  • the injections can be administered intravenously, subcutaneously and/or intramuscularly.
  • suspending agents are methylcellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethylcellulose, and polyoxyethylene sorbitan monolaurate; preferred examples of solubilizers are polyoxyethylene hardened caster oil, polysorbate 80, nicotinamide, and polyoxyethylene sorbitan monolaurate; preferred examples of the stabilizers are sodium sulfite, sodium metasulfite, and ether; preferred examples of the preservatives are methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
  • Base materials for use herein can be any raw materials generally used in, for example, pharmaceutical preparations, quasi drugs, and cosmetics.
  • Such raw materials include, for example, animal or vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicon oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, and purified water.
  • any of pH adjusting agents, antioxidants, chelating agents, antiseptics and antimolds, coloring agents, and flavors can be added.
  • components having differentiation-inducing action, blood-flow accelerators, bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, humectants, keratolytic agents, and other components can be added according to necessity.
  • the dose of the pharmaceutical preparation according to the present invention varies depending on the degree of symptom, age, sex, body weight, administration mode, type of the salt, difference in sensibility to the drug, concrete type of the disease, and other factors.
  • the pharmaceutical preparations may be administered at a daily dose of about 30 ⁇ g to about 1000 mg, preferably about 100 ⁇ g to about 500 mg, and more preferably about 100 ⁇ g to about 100 mg for an adult in one to several divided doses.
  • they may be administered at a daily dose of about 1 to about 3000 ⁇ g/kg, and preferably about 3 to about 1000 ⁇ g/kg for an adult in one to several divided doses.
  • the present invention can provide novel indazole compounds.
  • the compounds (I) according to the present invention or the salts thereof have excellent inhibitory action on c-Jun amino-terminal kinases, especially on JNK 3. Accordingly, the compounds (I) according to the present invention or the salts thereof, and pharmaceutical compositions containing the same are useful as therapeutic agents or prophylactic agents for an immunologic disease, inflammatory disease and/or neurodegenerative disease.
  • neurodegenerative diseases such as acute stage of cerebrovascular disorder, head injury, spinal code injury, neuropathy due to hypoxia, and neuropathy due to hypoglycemia; chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis or spinocerebellar degeneration; epilepsy; hepatic encephalopathy; peripheral neuropathy; Parkinsonian syndrome; spastic paralysis; pain; neuralgia; infectious encephalomyelitis; cerebrovascular dementia; or dementia or neurological symptom due to meningitidis.
  • acute neurodegenerative diseases such as acute stage of cerebrovascular disorder, head injury, spinal code injury, neuropathy due to hypoxia, and neuropathy due to hypoglycemia
  • chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis or spinocerebellar degeneration
  • epilepsy hepatic ence
  • the product was dissolved in 150 ml of dry tetrahydrofuran. After cooling to -78°C in an atmosphere of nitrogen gas, 59 ml of a 2.5 M solution of n-butyllithium in hexane was added. After stirring for 30 minutes, 12.7 ml of 3-fluorobenzaldehyde was added and the mixture was heated to room temperature. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated.
  • the title compound was also synthetically prepared by another procedure as mentioned below.
  • a total of 2.0 g of [5-(dimethoxymethyl)-2-fluorophenyl](3-fluorophenyl)methanol was dissolved in 20 ml of dichloromethane, and the solution was treated with 5 g of manganese dioxide with stirring at room temperature for one day.
  • the reaction mixture was filtrated using a Celite, the solvent was removed by distillation under reduced pressure, to give 2.0 g of the title compound.
  • a total of 2.49 g of 3-bromo-4-fluorobenzaldehyde dimethylacetal produced in Production Example I-4-a was dissolved in 20 ml of dry tetrahydrofuran. After cooling to -78°C in an atmosphere of nitrogen gas, 8.5 ml of a 1.56 M solution of n-butyllithium in hexane was added. After stirring for 30 minutes, 1.0 ml of N,N-dimethylformamide was added and the mixture was heated to room temperature. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate for two times.
  • a total of 303 mg of the title compound was obtained as light brown crystals by the procedure of Production Example I-17-a, except from 500 mg of tert -butyl 3-bromo-5-cyano-1 H -1-indazolecarboxylate produced in Production Example I-14-b and 415 mg of 3-benzo[b]thiopheneboronic acid.
  • the reaction mixture was added with 250 ml of ethyl acetate, sequentially washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was removed.
  • the residue was recrystallized from ethyl acetate-diisopropyl ether, to give 7.44 g of the title compound as white needles.
  • Example I-1 A total of 36 mg of the title compound was obtained as white needles by the procedure of Example I-1, except from 60 mg of 3-(3-chlorophenyl)-1 H -5-indazolecarboxylic acid produced in Production Example I-15 and 35 mg of 3-picolylamine.
  • Example I-1 A total of 28 mg of the title compound was obtained as white crystals by the procedure of Example I-1, except from 53 mg of 3-[3-(trifluoromethyl)phenyl]-1 H -5-indazolecarboxylic acid produced in Production Example I-16 and 28 mg of 3-picolylamine.
  • Example I-1 A total of 8 mg of the title compound was obtained as a white amorphous powder by the procedure of Example I-1, except from 14 mg of 3-(3-methoxyphenyl)-1 H -5-indazolecarboxylic acid produced in Production Example I-18 and 12 mg of 3-picolylamine.
  • Example I-1 A total of 50 mg of the title compound was obtained as a colorless powder by the procedure of Example I-1, except from 150 mg of 3-(3-fluorophenyl)-1 H -5-indazolecarboxylic acid produced in Production Example 1-4 and 1.2 ml of 0.5 M solution of valinol in acetonitrile as starting materials.
  • Example I-1 A total of 20 mg of the title compound was obtained as a colorless powder by the procedure of Example I-1, except from 50 mg of 3-(3-fluorophenyl)-1 H -5-indazolecarboxylic acid produced in Production Example 1-4 and 30 mg of R(-)-2-phenylglycinol as starting materials.
  • Example I-7 A total of 16 mg of the title compound was obtained as a colorless powder by the procedure of Example I-7, except from 180 mg of 3-(3-fluorophenyl)-1 H -5-indazolecarboxylic acid produced in Production Example I-4 and 115 mg of 1-amino-1-cyclopentanemethanol as starting materials.
  • Example I-7 A total of 75 mg of the title compound was obtained as a colorless powder by the procedure of Example I-7, except from 180 mg of 3-(3-fluorophenyl)-1 H -5-indazolecarboxylic acid produced in Production Example 1-4 and 137 mg of 2-amino-1-phenylethanol as starting materials.
  • Example I-7 A total of 60 mg of the title compound was obtained as a colorless oily substance by the procedure of Example I-7, except from 180 mg of 3-(3-fluorophenyl)-1 H -5-indazolecarboxylic acid produced in Production Example I-4 and 0.08 ml of 1-amino-2-propanol as starting materials.
  • Example 1-7 A total of 55 mg of the title compound was obtained as a colorless powder by the procedure of Example 1-7, except from 180 mg of 3-(3-fluorophenyl)-1 H -5-indazolecarboxylic acid produced in Production Example 1-4 and 112 mg of 2-amino-2-(4-chlorophenyl)-1-ethanol as starting materials.
  • Example 1-7 A total of 80 mg of the title compound was obtained as a colorless powder by the procedure of Example 1-7, except from 162 mg of 3-(3-fluorophenyl)-1 H -5-indazolecarboxylic acid produced in Production Example 1-4 and 130 mg of 2-amino-2-[4-(trifluoromethyl)phenyl]-1-ethanol as starting materials.
  • Example I-7 A total of 40 mg of the title compound was obtained as a colorless oily substance by the procedure of Example I-7, except from 180 mg of 3-(3-fluorophenyl)-1 H -5-indazolecarboxylic acid produced in Production Example 1-4 and 0.08 ml of 3-amino-1,2-propanediol as starting materials.
  • Example I-7 A total of 51 mg of the title compound was obtained as a colorless powder by the procedure of Example I-7, except from 180 mg of 3-(3-fluorophenyl)-1H-5-indazolecarboxylic acid produced in Production Example I-4 and 155 mg of 2-(2-fluorophenyl)glycinol as starting materials.
  • Example I-15 A total of 20 mg of the title compound was obtained as a colorless powder by the procedure of Example I-15, except from 120 mg of tert -butyl 5-amino-3-(3-fluorophenyl)-1 H -1-indazolecarboxylate produced in Production Example I-26 and 0.05 ml of 2-thiopheneacetic acid chloride as starting materials.
  • Example I-18 A total of 26 mg of the title compound was obtained as a colorless powder by the procedure of Example I-18, except from 50 mg of tert -butyl 5-amino-3-(3-fluorophenyl)-1 H -1-indazolecarboxylate produced in Production Example I-26 and 0.02 ml of 2,2,2-trifluoro-1-ethanesulfonyl chloride as starting materials.
  • Example I-18 A total of 35 mg of the title compound was obtained as a colorless powder by the procedure of Example I-18, except from 50 mg of tert -butyl 5-amino-3-(3-fluorophenyl)-1 H -1-indazolecarboxylate produced in Production Example I-26 and 30 mg of p-toluenesulfonyl chloride as starting materials.
  • Example I-18 A total of 30 mg of the title compound was obtained as a colorless powder by the procedure of Example I-18, except from 50 mg of tert -butyl 5-amino-3-(3-fluorophenyl)-1 H -1-indazolecarboxylate produced in Production Example I-26 and 30 mg of 4-morpholinecarbonyl chloride as starting materials.
  • Example 1-7 A total of 11 mg of the title compound was obtained as a colorless powder by the procedure of Example 1-7, except from 50 mg of ( E )-[3-(3-fluorophenyl)-1 H -5-indazolyl]-2-propenoic acid produced in Production Example I-25 and 18 mg of S(+)-2-phenylglycinol as starting materials.
  • a total of 30 mg of the title compound was obtained as a colorless oil by the procedure of Production Example I-25-a, except from 160 mg of tert -butyl 3-(3-fluorophenyl)-5-formyl-1 H -1-indazolecarboxylate produced in Production Example I-25-a and 0.58 ml of a 1.04 N solution of phenyllithium in cyclohexane as starting materials.
  • a total of 96 pieces of a polystyrene resin (SunPhase Polystyrene D-Seriese, TritylTM ) labeled with TRANSTEMTM was left stand in 100 ml of a 10% solution of acetyl chloride in methylene chloride for 3 hours. After removing the solution, the residue was washed with three portions of methylene chloride and dried in vacuo.
  • the resin was heated in a solution of 15 g of 3-bromo-5-nitro-1 H -indazole produced in Production Example I-26-a and diisopropylamine in 150 ml N-methylpyrrolidone at 80°C for 4 hours. After removing the solution, the resin was sequentially washed with N-methylpyrrolidone, ethanol, water, methanol and tetrahydrofuran, and dried in vacuo.
  • the resulting resin was divided among 8 groups (each 12 pieces) according to its label and was added to 15 ml of a solution of 0.5 M boronic acid in N-methylpyrrolidone of eight types previously prepared, respectively.
  • Each reaction mixture was treated with 1.5 ml of a 0.5 M solution of 2-(di- tert -butylphosphino)biphenyl in N-methylpyrrolidone, 1.8 ml of a 8 M aqueous solution of potassium fluoride, and a catalytic amount of palladium(II) acetate by heating at 80°C for 12 hours.
  • the resin was washed according to the above procedure and was dried under reduced pressure.
  • the resin was heated in 150 ml of a 2 M solution of stannic chloride in N-methylpyrrolidone at 80°C for 4 hours. After removing the solution, the resin was washed according to the above procedure and was dried in vacuo.
  • the resin was further divided among 12 groups (each 8 pieces) according to its label and was added to 15 ml of a solution of 0.5 M carboxylic acid in N-methylpyrrolidone of twelve types previously prepared, respectively.
  • WSC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • WSC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • diisopropylethylamine In a sulfonamide compound, a sulfonyl chloride reagent and diisopropylethylamine were added in tetrahydrofuran.
  • the mixture was subjected to sonication for 1 hour and was left stand at room temperature for one day. After removing the solution, the resin was washed according to the above procedure and was dried under reduced pressure. The resin was placed in each of 96-well pin plate according to its label.
  • a mixture solution of 0.5 ml of trifluoroacetic acid, 0.1 ml of triisopropylsilane, and 0.5 ml of dichloromethane previously prepared was added to the resin in each of the 96-well plate, and the mixture was subjected to sonication for 10 minutes and was left stand for 30 minutes. This procedure was repeated twice, and the resin was washed with 1 ml of dimethylformamide.

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EP1380576A4 (de) 2005-02-16
EP1380576B1 (de) 2009-11-25
CA2440842A1 (en) 2002-10-24
US20040127538A1 (en) 2004-07-01
ATE449763T1 (de) 2009-12-15
US7541376B2 (en) 2009-06-02
JP4535680B2 (ja) 2010-09-01
DE60234510D1 (de) 2010-01-07
US20050282880A1 (en) 2005-12-22
KR20040007497A (ko) 2004-01-24
CN1512987A (zh) 2004-07-14
JPWO2002083648A1 (ja) 2004-08-05
WO2002083648A1 (en) 2002-10-24
AU2002255263B2 (en) 2006-12-14
CN1300116C (zh) 2007-02-14
US20090203691A1 (en) 2009-08-13
US7776890B2 (en) 2010-08-17
US6982274B2 (en) 2006-01-03

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